The Carcinogenic Effects of Formaldehyde Occupational Exposure: A Systematic Review

Simple Summary Formaldehyde is a chemical compound present in many working activities and indoor workplaces. Occupational exposure occurs primarily by inhaling airborne formaldehyde, but it can also be absorbed through the skin or ingested. The International Agency for Research on Cancer (IARC) classified formaldehyde as a Group 1 carcinogen for humans in 2004, based on toxicological data and epidemiological evidence obtained in workplaces, all published before that year. Over the last two decades, many new studies in this field have been published, providing updated findings. The aim of the present systematic review was to synthetize the results of epidemiological studies in occupational settings carried out in the last 20 years and to evaluate whether the IARC classification was confirmed by further studies. Our results show that the evidence of correlation between formaldehyde occupational exposure and the occurrence of cancer is limited. Abstract Background: Formaldehyde, classified as a carcinogen in 2004, as of today is widely used in many work activities. From its classification, further studies were performed to evaluate its carcinogenicity. The aim of the systematic review is to update the evidence on occupational exposure to formaldehyde and cancer onset. Methods: The review, in accordance with the PRISMA statement, includes articles in English reporting original results of studies conducted on workers exposed to formaldehyde, considering all types of cancer, published from 1 January 2000 to 30 July 2021 and selected from the Pubmed and Scopus databases. The studies’ quality was assessed by the Newcastle–Ottawa Scale. Results: A total of 21 articles were included, conducted in different European, American, and Asian countries. The most investigated occupational areas are those characterized by a deliberate use of formaldehyde. Some studies evaluated all types of cancer, whereas others focused on specific sites such as thyroid and respiratory, lymphohematopoietic, or central nervous systems. The results showed weak associations with lung cancer, nasopharyngeal cancer, leukemia, and non-Hodgkin’s lymphoma. Conclusions: The results demonstrate the need for further original studies carried out on representative samples of workers exposed to measured levels of FA. These studies should be designed to reduce the bias due to co-exposure to other carcinogens.


Introduction
Formaldehyde (FA) is a chemical compound naturally occurring in the atmosphere, in some foods, and in the organisms of mammals as a product of oxidative metabolism and, in any database and, then, it was too late to do it because the protocol registration must be performed before the start of the review process. Zotero citation management software (RRID:SCR_013784) was used to identify any duplicates and to manage and screen the identified records.

Literature Research
The review includes articles published in the last 20 years, from 1 January 2000 to 31 July 2021, on the databases Pubmed and Scopus. The search strategy used a combination of controlled vocabulary and free text terms based on the following keywords: "formaldehyde", "cancer", "tumor", "neoplasm", "occupational", and "exposure". Additionally, a hand search of the reference lists of the selected articles was carried out for a wider analysis. Four independent reviewers (V.C., R.N.P., D.M. and G.B.) performed the search, reading the titles and abstracts of the articles identified by the search strategy.
During the multi-step exclusion process, any disagreement on the studies was discussed until consensus. The process was supervised by other investigators (C.P. and M.V.). Figure S1 (Supplementary Materials) shows the flow chart summarizing the selection steps for the systematic review.

Inclusion and Exclusion Criteria
The review included only studies in which the participants were classified as "exposed to formaldehyde." The exposure assessment was considered acceptable if performed by direct (personal or environmental) sampling of FA, occupational history data, or job exposure matrix. Cancers were classified using the International Classification of Diseases, Tenth Revision (ICD- 10).
Only studies involving humans (men and/or women) exposed to FA in occupational settings, reporting results for any kind of cancer and published in peer-reviewed journals, were selected. Searches providing no information about the exposure assessment method or with a self-assessment by the participants were excluded. Besides, we excluded reviews, editorial articles, individual contributions (i.e., conference speeches), and purely descriptive studies published in scientific conferences without any quantitative or qualitative conclusions. Finally, articles published in languages other than English were excluded.

Data Analysis
From each study included in the review, the following data were extracted: publication year, exposure time period, study design, working population studied, cancer type (ICD-10 classification), exposure assessment, and main conclusions.

Quality Evaluation
Four different reviewers (V.C., R.N.P., D.M. and G.B.) assessed the methodological quality of the selected studies with a specific rating tool, the Newcastle-Ottawa Scale (NOS), adapted for evaluating case-control, cross-sectional, and cohort studies [37]. It is divided into eight categories checking three quality aspects: selection, comparability and outcome/exposure; scores range from 0 to 9. The quality of a study was considered to be high if the NOS score was 7 to 9, intermediate if the NOS score was 4 to 6, and low if it was 0 to 3.

Results
In total, we recovered 1029 studies from all searched databases (n = 629 from Scopus and n = 400 from Pubmed) and, after applying filters by automation tools, 390 articles remained. Out of the remaining 390 papers, 350 were excluded after removing duplicates. Successively, one more paper was removed after reading the abstract. Then, the full texts of 39 studies were checked and evaluated considering the inclusion/exclusion criteria. A total of 14 papers were then excluded because they did not fit the inclusion criteria. Besides, eight articles were based on the same studied cohort; thus, we considered only the most recent, excluding those previously published. Six articles were found via citation search and four were included after checking their eligibility, whereas two were discarded due to the difficulty of extrapolating FA exposure. At the end of the process, 21 articles were included in the systematic review . The PRISMA Flow Diagram is available as Supplementary Materials ( Figure S1). Table 1 shows the characteristics of the studies included, with reference to country, workers' gender, sample size, working context, study period, smoking adjustment, exposure assessment, cancer type, and main conclusions.

Characteristics of the Included Studies
The studies included were conducted on almost all continents, with six from Europe, nine from North America, four from Asia, one from South America, and one multicenter study. Most (11 studies) involved both sexes, seven involved only males, and three only females. In total, 11 case-control studies, eight cohort studies, and two case-cohort studies were considered. Industry and manufacturing were the most examined working contexts, in particular the sectors of chemical, plywood, and textile production. Therefore, the majority of the studies included (n. 11) regarded workers exposed to FA in several working contexts and workplaces. Twelve studies considered smoking a confounding factor and adjusted the results accordingly. Only three research groups performed the direct exposure assessment through personal or environmental sampling; the others assessed the exposure level indirectly by job exposure matrix or occupational history data. Five studies looked for the relationship between FA exposure and the onset of any cancer, seven evaluated the onset of upper airway cancers, four focused on lung cancer, two focused on lympho-hematopoietic cancers, one focused on thyroid cancer, and one focused on meningioma. The sample size was very variable, ranging from two cases and five controls in the smallest case-cohort study to a cohort of 1.2 million workers in the study by Siew et al. [51].

Scoring Results
The median NOS score of the included studies was 7, thus indicating a high average quality level. Table 2 shows the results of the scoring method applied to each study included in the review, with reference to publication year, study design, and main statistical results achieved (expressed as odds ratio, hazard ratio, relative risk, or standardized mortality ratio and with a 95% confidence interval). Results support a possible relation between FA exposure and myeloid leukemia mortality. Non-significant excesses in mortality were observed among FA-exposed workers for several other cancers. Overall, the pattern of findings suggests that the large, persistent nasopharyngeal and other PC excesses observed were not associated with FA exposure. Interaction models suggest that NPC and AOPC risks were not elevated in subjects exposed only to FA. Exposure to FA was found to be associated with an increased risk of NHL in our study, but the risk was mainly for those with a low exposure intensity or probability. For all cancer, solid tumors, and lung cancer, the mortality among exposed workers was high, but internal analyses revealed no positive associations with FA exposure. Consistent with previous analyses of this cohort, this update continues to suggest a link between FA exposure and nasopharyngeal cancer. Our results provide no support for an increased hazard of myeloid leukemia, nasopharyngeal carcinoma, or other upper airway tumors from FA exposure. These results indicate that any excess risk of these cancers, even from relatively high exposures, is at most small. This study shows an increased risk in relation to FA based mainly in women in relation to a duration of exposure of more than 15 years and highest cumulative exposure, although neither of the trends was statistically significant.
* Both cases and controls exposed to formaldehyde; ** direct exposure assessment.

Discussion
We performed a systematic review on the association between FA occupational exposure and the occurrence of cancer in potentially exposed workers.
Previous studies about FA and cancer risk suggested a modest excess of risk for nasopharyngeal cancer [59], but the studied cohort of workers was co-exposed to several other chemicals, resulting in additive and/or synergic effects or misleading results. Despite this, the findings were included by the IARC in its evaluation, even if subsequent analysis revealed no statistical significance of these results and highlighted the inappropriateness of the adopted exposure assessment approach [60].
Among the studies included in our review, we found a direct assessment of the exposure levels of FA only in three papers. In the other cases, the exposure assessment was indirectly extrapolated considering the length of exposure and the type of activities performed (e.g., job exposure matrix). Most of the studies included in this review dealt with occupational settings, characterized by a deliberate use of FA as a component of the production cycle. Those were mainly represented by chemical industries dedicated to the production of plastics, fiberglass, paints, etc.; it is reasonable to imagine that in such contexts the levels of exposure to FA were particularly high. Three studies were carried out in textile-/garment-producing plants, where FA is used to give resistance to the folds of clothing fabrics and for the processing of leathers. Another sector where this substance is widely used is that of woodworking and furniture making. In fact, FA, together with resins, gives strength and resistance to chipboard panels. FA is also widely used in the medical field: in the operating room it was used to disinfect instruments because of its high antibacterial power, and even today, it is used to avoid the deterioration of human tissues that must undergo histopathological analyses. Despite that, very few studies concerned the health sector, or the agri-food industry, where FA is used as a preservative. That is quite surprising, considering that there is much research about the occupational exposure to FA in pathological anatomy settings and sector rooms [61][62][63] that stress the needing for adequate preventive measures for workers [64].
Although the genotoxicity and immunotoxicity of FA is well known and has been demonstrated by several studies regarding its influence on DNA and pro-oxidative effects on cells [28,[65][66][67][68][69][70][71][72], the evidence from human studies and diagnosed cancers is much less consistent [73]. Most of the studies included in this review focus on upper-airway neoplasms (ICD-10 codes: C10-C14 and C30-C33), as mentioned previously. In fact, the main way of entry of this substance into the body is by inhalation. Five studies explored the relationship between FA occupational exposure and the onset of lung cancer (ICD-10 code: C34). Their findings contrasted with each other: some did not provide evidence of a carcinogenic effect on the lungs [42,51,52], whereas others found a correlation [44,49]. These last studies, however, were performed on a very small sample and present several limitations (e.g., self-reported data on exposure levels). A recent meta-analysis by Kwak et al. [31] concluded no significant increase in the risk of lung cancer, even considering only groups of highly exposed workers. The small study sample of the study by Checkoway et al. about lung cancer was also checked for thyroid cancer, with some relationships found but with the same, considerable, limitations [46]. In 2012, the IARC affirmed that there was strong but insufficient evidence of a causal relationship with leukemia. Two studies included in our review regarded the relationship between FA exposure and lympho-hematopoietic cancers (ICD-10 codes: C81-C96), but no association was observed for all leukemias [56], except for a small and weak association with non-Hodgkin lymphoma [48] and myeloid leukemia [50]. This is consistent with the results of other previous studies [30,33]. Five of the included publications evaluated the effects of FA occupational exposure on the onset of any kind of cancer. These were large cohort studies, carried out in Europe and the USA in industrial contexts, and almost all concluded no positive association with FA exposure and the mortality from any cancer, and very limited evidence with NPC and leukemia [43,[53][54][55][56]. The most recent research included, published in 2018, was a multicenter study about FA and meningioma. Meningiomas are tumors that develop from the meninges, tissues that surround the outside of the brain and account for about 30% of brain tumors. Although benign, they are dangerous because dysphagia, dysarthria, ocular motility disorders, and facial numbness can occur. Intracranial hypertension, focal seizures, lack of strength, and balance and gait disturbances may also sometimes occur. The study concluded that FA did not provoke excess risks of meningioma [58].
The present systematic review has some limitations. First of all, we considered only papers published in the last 20 years, but this choice was driven by the aim of the present systematic review. Secondly, we considered only articles published in the English language, excluding a priori potentially useful results published in other languages. Finally, we did not perform a formal meta-analysis because the studies included in the review were different in terms of exposure assessment methodologies, kind of cancers considered, and study design. For this reason, statistical heterogeneity and publication bias were not evaluated. Our choice is well supported by a very recent official statement by Cochrane on the opportunity for performing a meta-analysis when data are heterogeneous: "Metaanalysis should only be considered when a group of studies is sufficiently homogeneous in terms of participants, interventions and outcomes to provide a meaningful summary. It is often appropriate to take a broader perspective in a meta-analysis than in a single clinical trial. A common analogy is that systematic reviews bring together apples and oranges, and that combining these can yield a meaningless result" [74].

Conclusions
FA has been classified by the IARC as a Group I carcinogen since 2004; this classification was based on evidence obtained in preceding years. Reviewing the scientific literature published in the last 20 years, we found at least 21 additional epidemiological studies on the association between occupational exposure to FA and cancer onset. This finding indicates the need for an update of the FA classification based on the new evidence. On the other hand, the results of the examined papers do not completely confirm the IARC classification of FA and give contrasting results. Thus, it is essential to perform further original studies carried out on representative samples of workers exposed to measured levels of FA. These studies should be designed to reduce bias as much as possible due to co-exposure to other carcinogens.